P1241: A NOVEL CEREBLON-BINDING MOLECULAR GLUE, SP-3164, SHOWS PRECLINICAL ACTIVITY IN NON-HODGKIN LYMPHOMAS
Authors: Daniela Santiesteban, Aundrietta D. Duncan, Nadeem Q. Mirza, Stephen Horrigan, Sheila Dewitt, Vincent Jacques, Swaminathan P. Iyer
Journal: HemaSphere (2023)

Topic: 20. Lymphoma Biology & Translational Research Background: Relapsed and refractory non-Hodgkin’s lymphomas (NHLs) are an area of high unmet need with patients seeking novel, chemotherapy-free options. One modality that has shown potential for treatment of NHLs is targeted protein degradation (TPD). The first-generation cereblon (CRBN)-binding molecular glue, lenalidomide, is used for treatment of various NHLs including mantle cell, follicular, and diffuse large B-cell lymphomas. SP-3164 is a next-generation CRBN-binding molecular glue with the potential for improved therapeutic and safety properties due to its novel use of deuterium-enabled chiral switching (DECS). To date, the majority of CRBN-binding molecular glues, including lenalidomide, pomalidomide, and avadomide, are glutarimides with an unstable chiral center that results in interconversion between the desired, active (S)-enantiomer and the inactive (R)-enantiomer. DECS stabilizes the chiral center and allows for the characterization of SP-3164, the stable, active (S)-enantiomer of avadomide. SP-3164 can potently degrade Ikaros and Aiolos (I/A), showing compelling activity in preclinical NHL models. Previously, we demonstrated SP-3164’s differential activity compared to other I/A degraders and have shown that the (R)-enantiomer (SP-3165) does not induce protein degradation in cancer cells, resulting in minimal therapeutic activity. Instead, SP-3165 appears to support tumor growth in certain xenograft models. Additionally, we showed SP-3164’s potent activity in an in vivo DLBCL model as a single agent and in combination with rituximab. Aims: To further characterize SP-3164’s protein degradation and anticancer activity and demonstrate its therapeutic potential in NHLs, including follicular lymphoma (FL). Methods: Degradation of I/A in peripheral blood mononuclear cells (PBMCs) at various SP-3164 concentrations (10, 100, 1000 nM) and time points (2, 4, 6, and 24 hours) was assessed via Western blots. Additional in vitro studies included viability and cytokine secretion assays. In vivo bioavailability studies were conducted in BALB/c mice and xenograft studies were conducted in NOD/SCID mice. Results: Degradation of I/A in PBMCs was dose- and time-dependent, with >70% degradation being achieved at 24 hours across all tested concentrations and the 1000 nM treatment group achieving >70% degradation as early as 2 hours (PBMC viability was not affected following up to 96 hours of SP-3164 treatment). In addition to having direct anti-tumor effects, I/A degraders also exert anticancer effects via immunomodulation, which is critical for therapeutic activity in lymphomas. To study SP-3164’s immunomodulatory effects, we treated T-cells with SP-3164 or SP-3165 and examined the response in a panel of cytokines. SP-3164 stimulated cytokine release (i.e., IL-2 and TNF-α) at significantly lower concentrations than SP-3165. Pharmacokinetic studies demonstrated that SP-3164 was highly bioavailable (F >100%). In an in vivo efficacy model of FL (DOHH2), SP-3164 (7.5 mg/kg BID PO) showed significant tumor growth inhibition (TGI) compared to vehicle. In addition, the combination of SP-3164 with venetoclax (50 mg/kg QD PO, 5 on/2 off) resulted in more significant TGI than either SP-3164 or venetoclax alone (Figure). Summary/Conclusion: SP-3164 is a novel, orally available, CRBN-binding molecular glue with potent immunomodulatory activity and attractive therapeutic properties in NHL models, including FL. Further assessment of SP-3164’s potential as a treatment for NHLs is warranted and a clinical trial is planned to start in 2023. Mouse FL (DOHH2) Xenograft Model Tumor Volume ±SEM *** ***p ≤0.001Keywords: Non-Hodgkin’s lymphoma, Immunomodulation, B cell lymphoma